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SUMMARY

Regulation of Cardiovascular Ion Channels

The major focus of our research is to understand the regulation of ion channels in the cardiovascular system. In the heart, ion channel activities regulate the configuration of cardiac action potential, electrical impulse generation and propagation. In blood vessels, ion channels regulate vascular tone and blood flow to organs and tissues. Abnormal ion channel regulation is known to result in cardiac arrhythmias, abnormal blood pressures, and organ perfusion. We use patch clamp and microelectrode techniques to measure action potentials and ionic currents in cardiovascular tissues and cells. We use biochemical and molecular approaches to examine the expression, cellular trafficking, and membrane microdomain targeting of ion channels, and use site-directed mutagenesis techniques to examine structure-function relationships in ion channel regulation.

Specific current research projects include the following:

Regulation of cardiac and vascular ATP-sensitive potassium (KATP) channels by lipid metabolites with special focus on the cytochrome P450 monooxygenase metabolites of arachidonic acid.

Regulation of the vascular large conductance calcium-activated potassium (BK) channels by endothelium-derived hyperpolarizing factors (EDHFs). EDHFs are critical elements that regulate the reactivity of resistance vessels by their effects on BK channels which are major determinants in vasorelaxation.

Molecular mechanism of ion channel redox modulation by reactive oxygen species. Both KATP and BK channels are profoundly modulated by oxidative stress and both superoxide and hydrogen peroxide react with specific amino acid residues on the ion channels through redox reactions.

Molecular mechanisms underlying ion channelopathy and vasculopathy in diabetes. Diabetes mellitus has become an epidemic and this condition is associated with serious vascular complications including coronary artery disease, hypertension, stroke, and microvascular diseases that involve the retina and kidneys. Derangements in the regulation of vascular ion channels are found at several levels including the biosynthetic pathways that produce ion channel activators but also on the intrinsic biophysical properties of the channels.

Novel motifs of ion channel regulation including membrane microdomain targeting of ion channels in cardiovascular tissues including the vascular endothelium.

Novel approaches in the treatment of cardiac arrhythmias including cellular therapies.

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